yielded compound EED226 (30, Fig. 3) [65], a potent and selective PRC2-EZH2/
PRC2-EZH1 disruptor, reducing global H3K27me3 in cells, able to kill selectively
cells with a heterozygous Y641N mutation. This compound showed optimal PK
properties, encouraging and enabling extensive preclinical studies, demonstrating an
optimal tolerability in various species, also inducing regression of tumor xenografts
in vivo [65]. Notably, this compound is even effective in cell lines with acquired
resistance to SAM-competitive EZH2 inhibitors and shows a synergistic effect when
combined with EZH2 inhibitors [67]. Compound 31 (Fig. 3), MAK-683, structurally
related to compound 30, is currently in phase I/II clinical trials for diffuse large B-cell
lymphoma nasopharyngeal carcinoma [56]. Compound 31 has been described in a
patent in 2017 without giving details on its precise biological activity [70] in contrast
to compound 30, which has been described in various contexts [65, 67].
N
N
NH
N
F
O
23, Astemizole
K i : 23.01 mM
O
O
O
HO
O
HO
HO
24, wedelolactone
K D : 2.82 mM
N
N
N N
NH
O
S
O
O
32
IC 50 : 1.3 mM
N
N
H 2 N
F
O
N
H
O
H
O
25, EED210
IC 50 : 0.89 mM
N
N
NO 2
N
26, EED666
IC 50 : 8.76 mM
N
N
N
O
27, EED709
IC 50 : 1.57 mM
N
N
N N
NH
O
N
28, EED162
IC 50 : 0.32 mM
N
O
O
NH
O
O
N
29, EED396
IC 50 : 11.58 mM
30, EED226
IC 50 : 0.022 mM
F
N
N
N
N
H 3 CO 2 S
33, A395
K i : 0.4 nM
H
N
O
N
H
N
H
O
H
N
O
NH 2
O
N
34, UNC5114
IC 50 : 1.74 mM
H
N
O
N
H
N
H
O
N
35, UNC5115
IC 50 : 3.87 mM
O
N
N
N
N N
NH
N
31, MAK683
IC 50 : nA
F
O
Fig. 3 PRC2 disruptors
134
G. Stazi et al.